tbuckley/cabot-search huggingface dataset:
NCOG-22. SEIZURE OUTCOME ACROSS DISEASE TRAJECTORY IN <i>IDH</i>-MUTANT GRADE 2 GLIOMAS: WHICH IS THE IMPACT OF STANDARD ANTINEOPLASTIC TREATMENTS?
Authors: Francesco Bruno, Alessia Pellerino, Marco Conti Nibali, Edoardo Pronello, Luca Bertero, Diego Garbossa, Lorenzo Bello, Roberta Rudà
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Most patients with IDH-mutant grade 2 gliomas suffer from seizures. Recently, the INDIGO trial showed that vorasidenib prolonged progression-free-survival (PFS) and time-to-next-intervention in IDH-mutant grade 2 gliomas after surgery. We investigated which factors influence seizure-control in patients with the same characteristics of those of INDIGO. Patients and METHODS We retrospectively collected data of non-enhancing IDH-mutant grade 2 glioma patients (as per WHO-2021) who presented with seizures, and evaluated seizure-freedom at 2 months after surgery, 6 months from starting either observation or adjuvant treatments, at recurrence, and 6 months after treatment of recurrence. RESULTS Ninety-five patients were included. Oligodendrogliomas IDH-mutant/1p19q-codeleted grade 2 were 69 (72.6%), astrocytomas IDH-mutant grade 2 were 26 (27.4%). Thirty-five (36.8%) received gross-total resection (GTR). After surgery, 49 (51.6%) achieved seizure-freedom, more frequently after GTR vs non-GTR (57.9% vs 35.1%, p=0.048). Sixty-eight (71.6%) low-risk patients underwent observation, while 27 (28.4%) high-risk patients received adjuvant radiotherapy (RT) and/or chemotherapy (CT). Among the latter, 17/27 (63.0%) had persistent seizures before treatment initiation and, after 6 months, all of them displayed seizure-reduction, with 2/17 (7.4%) seizure-free. In a multivariable analysis on PFS, ≥ 50% seizure-reduction (vs &amp;lt; 50%) after 6 months of adjuvant treatment reduced the risk of progression (HR 0.048, 0.004-0.585, p=0.017). Eighty-six (90.5%) patients recurred, and 51/86 (59.3%) displayed seizures. After 6 months of treatment of recurrence, 50/51 (98.0%) achieved seizure-reduction, with 10/51 (19.6%) seizure-free. In a multivariable analysis, either CT or RT increased the probability of seizure-freedom at 6 months after recurrence (HR 5.316, 1.582-17.869, p=0.007). CONCLUSION We defined the entity of seizure-control after standard treatments throughout the disease course. Two findings are noteworthy: the prognostic importance of seizure-reduction after adjuvant treatments; the possibility to achieve seizure-control also with treatment of recurrence. This study could serve as a benchmark for future evaluation of seizure-control with IDH inhibitors.
NCMP-09. THE CURRENT LANDSCAPE OF SPINE ONCOLOGY SURGICAL TRIALS AND FUTURE OPPORTUNITIES
Authors: Alexander Schupper, Shrey Patel, Jeremy Steinberger, Isabelle Germano
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Clinical trials have allowed the discovery of successful therapeutic intervention for cancer patients. The current number of cancer patients in the US has increased with an incidence of 442/100,000 population and yet with decreased yearly mortality rate. Spine metastatic disease occurs in approximately 90% of patients with cancer. The aim of this study is to analyze the current landscape of spine oncology trials to identify future opportunities. METHODS To assess active and ongoing clinical trials in the treatment of metastatic spinal disease, the authors queried https://clinicaltrials.gov/ under the searches “Spine Metastases” and “Spine Tumor.” Only clinical trials designated as “Recruiting” were included. Parametric and non-parametric statistical analysis was performed. RESULTS Our initial search yielded to 100 total studies; 18 clinical trials met entry criteria. Trial type was 16/18 therapeutic, 2/18 observational and trial design 6/18 (33%) randomized. All 18 trials were single center. Trials were were based in the United States (90%) and British Columbia, Canada. Across US geographical quadrants, a significant higher number of therapeutic trials was found in the South quadrant (12/16) compared to the other quadrants, (p&amp;lt; 0.001; Midwest: N=3/16, Northeast: N=1). The most common therapeutic focus included radiosurgery, followed by vertebral body augmentation and/or radiofrequency ablation, and laser interstitial thermal therapy (LITT). CONCLUSION Clinical trials are a cornerstone for the advancement oncological treatment. Our study shows that currently there is an ample opportunity to design clinical trials for our growing population of metastatic spine disease patients. Successful strategies to enhance the needed portfolio of spinal oncology trials, include focusing on including all US geographic quadrants. As new trials are designed, continued efforts devoted to data entry in national registry remains important.
NIMG-65. METHYLTHIOADENOSINE PHOSPHORYLASE STATUS CORRELATES WITH CLINICAL OUTCOME AND11C-METHIONINE UPTAKE IN ASTROCYTOMA, IDH-MUTANT
Authors: Toshihiro Yamamura, Kaoru Tamura, Daisuke Kobayashi, Motoki Inaji, Yuka Toyama, Shoko Hara, Yoji Tanaka, Tadashi Nariai, Juri Kiyokawa, Kenji Ishii, Taketoshi Maehara
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Methylthioadenosine phosphorylase (MTAP) immuno histochemistry staining has been proposed as a surrogate of Cyclin-dependent kinase inhibitor 2A homozygous deletion (CDKN2A HD) in various types of tumors. This study was designed to determine whether MTAP status correlates with clinical outcome and uptake of 11C-methionine in astrocytoma, IDH-mutant. METHODS We conducted a MTAP immunohistochemistry staining of 30 astrocytoma, IDH-mutant patients who underwent 11C-methionine positron emission tomography scans prior to surgical resection from 2000 to 2020. The tumor-to-normal (T/N) ratio of 11C-methionine uptake was calculated by dividing the mean standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. RESULTS Eight (26.7%) of the thirty astrocytoma, IDH-mutant patients exhibited loss of cytoplasmic MTAP expression, which is accompanied with a poor prognosis. The median progression free survival (PFS) in astrocytoma, IDH-mutant patients with loss of MTAP was 1.88 years and significantly shorter than that of those with MTAP retention (6.80 years, p = 0.003). The median Overall survival in astrocytoma, IDH-mutant patients with loss of MTAP was 5.23 years, again significantly shorter than that of those with MTAP retention (10.69 years, p = 0.0191). Multivariate analysis revealed that MTAP status was an independent prognostic marker for PFS in astrocytoma, IDH-mutant patients. The median T/N ratio in tumors with loss of cytoplasmic MTAP expression was 2.12 (IQR 1.92-2.50), i.e., significantly higher than that of tumors with MTAP retention (1.65, IQR 1.23-1.94, p = 0.0116, U test). Thirteen (59.1%) of twenty-two patients with MTAP retention recurred and nine patients underwent a second surgery after radiation treatment with or without chemotherapy. Three (33.3%) of the nine recurrent patients showed loss of MTAP immunoreactivity, suggesting a role for this loss in tumor progression. CONCLUSION Our study showed MTAP status to correlate with clinical outcome and T/N ratio of 11C-methionine in astrocytoma, IDH-mutant patients.
NIMG-19. TUMOR PARAMETERS AFFECTED BY NANOCOMBRESTATIN THERAPY IN AN EXPERIMENTAL RAT MODEL OF GLIOMA
Authors: Meser Ali, Ana deCarvalho, James Ewing, James Snyder, Tom Mikkelsen
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION: of polymeric nanoparticles in cancer therapeutics is widely investigated since nanomedicine often enables the intratumoral delivery of drugs with increased efficacy with minimal side effects. In this study magnetic resonance imaging (MRI) monitoring was employed to study the therapeutic effect of nanocombretastatin (G3-CA4) in an orthotopic glioma model. Water insoluble combretastatin (CA4) was conjugated to a small-sized water soluble G3-succinimic acid PAMAM dendrimer. Tumor growth and vascular parameters were assessed non-invasively using MRI. In the brain, intravenously (iv) administered magnetic resonance (MR) contrast agents (CAs) can be used to measure the biomarkers of tumor perfusion - the blood-to-brain transvascular transfer constant (K-trans), tumor plasma volume (Vp), the extravascular extracellular space (Ve) and the blood volume (VD) in cerebral tumors. K-trans, Vp, Ve and VD showed the discrimination of tumorous vasculature responding to CA4 and G3-CA4 therapies from tumorous tissues. The average K-trans, Vp, Ve and VD decreased significantly 24 hours after G3-CA4 treatment. The results showed that G3-CA4 caused a change in tumor vasculature as measured with DCE-MRI. These effects were homogenous throughout the U-251 tumor. However, CA4 did not show any change in tumor vasculature. Imaging, histological and molecular signatures of the primary glioblastoma were compared. Large necrotic area was found together with destroyed blood vessels at the core of the tumor leaving viable tissue at the rim of the tumor. In vivo studies proved that the cytotoxicity of G3-CA4 conjugate was more effective against human U-251 tumor while CA4 alone was ineffective. Therefore, we have accomplished the effective transvascular delivery of G3-CA4 into human U251 glioma tumor with a compromised blood brain tumor barrier. In vivo studies proved that the cytotoxicity of G3-CA4 conjugate is more effective against human U-251 tumor than that of free CA4.
PATH-62. RAMAN-BASED AI PLATFORM TO ACCELERATE THE DIAGNOSIS AND MANAGEMENT OF GLIOMAS VIA RAPID METHYLATION PROFILING
Authors: Adrian Lita, Joel Sjöberg, David Păcioianu, Nicoleta Siminea, Orieta Celiku, Andrei Păun, Mark Gilbert, Houtan Noushmehr, Ion Petre, Mioara Larion
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND DNA methylation profiling and subtyping of gliomas has become an integral part of the diagnosis and treatment of glioma patients but remains a challenge due to the sample preparation and time requirements of the existing methylation profiling technology. We hypothesized that machine learning and Raman spectroscopy, which creates fast molecular fingerprints of samples in situ based on chemical signatures rather than the use of exogenous dyes, can provide a fast alternative to the existing approaches for methylation profiling and classification of gliomas. METHODS Raman spectroscopy at the spatial resolution of less than 300nm was used for molecular fingerprinting of the regions of interest using 1mm2 Formalin-Fixed Paraffin-Embedded (FFPE) tissue spots from 45 patient samples with known LGm1 to LGm6 methylation subtypes. Spectral information (over 1738 frequencies) was used to construct tumor/non-tumor, IDH1WT/IDH1mut, and methylation-subtype classifiers. Oversampling was used to obtain subtype-balanced data distributions. Supervised wrapper methods and random forests were used to identify the top 20 most discriminatory Raman frequencies. Stimulated Raman spectroscopy was used to validate the findings. RESULTS We developed APOLLO - a novel platform based on spontaneous Raman spectroscopy and machine learning -- for predicting the DNA methylation subtypes of FFPE glioma tissue specimens. APOLLO discriminates tumors from non-tumor areas with 98% accuracy and discriminates IDH1mut versus IDH1WT tumors with 82% accuracy. APOLLO also achieved high discriminatory power between G-CIMP-high and G-CIMP-low molecular phenotypes (ROC of 0.75), subtypes of lower-grade IDH1mut gliomas with significantly different clinical outcomes. We determined that the Raman shifts important for discriminating IDH1mut versus IDH1wt tumors are associated with novel lipid-metabolism signatures of IDH1mut glioma. CONCLUSIONS The development of APOLLO allows fast, reliable, and accurate prediction of methylation subtypes of glioma which can speed diagnosis and, once validated on fresh tissue, can be implemented in the operating room.
NCOG-18. CLINICAL CHARACTERISTICS OF H3.G34 DIFFUSE HEMISPHERIC GLIOMA: A CASE SERIES AND REVIEW OF THE LITERATURE
Authors: Andrew Williams, Bryan Neth, Jian Campian, Gesina Keating, Sani H Kizilbash, Daniel Lachance, Michael Ruff, Jonathan Schwartz, Joon Uhm, John Atkinson, Terry Burns, David Daniels, Cody Nesvick, Ian Parney, William Breen, Paul Brown, Anita Mahajan, Elizabeth Yan, Ugur Sener
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Diffuse hemispheric glioma (DHG) is an uncommon infiltrating glioma, defined in the World Health Organization 2021 guidelines by a mutation in the H3F3A gene at codon 34 (H3.G34). DHG primarily affects children and young adults. Due to its rarity, there is paucity of knowledge regarding factors affecting overall survival (OS). We retrospectively assessed our institutional experience and present a review of the literature. METHODS We searched our institution’s pathology records to identify six cases of DHG. Demographic, clinical, diagnostic, treatment, and outcome data were recorded. We next searched for published articles regarding DHG cases via PubMed through May 2023. Four-hundred-fifty-four published individual cases of H3.G34 glioma were identified, 204 of which were hemispheric/supratentorial tumors with OS data reported, providing a combined 210 cases for analysis. 132 of these cases included MGMT promoter methylation status. 111 included extent of surgical resection. Kaplan-Meier and Cox regression survival analysis was performed. RESULTS Age range for DHG patients was 7-66 years (median 17). Median OS was 18.5 months (95% CI, 17-25). Greater extent of surgical resection and presence of MGMT promoter methylation were associated with better prognosis. Median OS for biopsy alone was 12 months (95% CI, 10-NA), subtotal resection was 16 months (95% CI, 14-23), and gross total resection was 27 months (95% CI 23-NA) – log-rank p&amp;lt; 0.001. OS for MGMT promoter unmethylated was 14 months (95% CI 12-22), MGMT promoter methylated was 24 months (95% CI, 17-30) – log-rank p=0.028. Contrary to previous reports, patient age was not found to impact prognosis (using 18, 21, and 40 years as cutoffs or as a continuous variable with Cox regression). CONCLUSION Extent of surgical resection and MGMT promoter methylation status are important prognostic factors for DHG. Unlike many primary brain tumors, survival does not appear to be significantly impacted by age.
MODL-01. INTRACRANIAL TUMORS HIJACK THE MENINGEAL VENOLYMPHATIC NETWORK THROUGH VEGFR-2 SIGNALING
Authors: D McGavern, Leonel Ampie
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Glioblastoma and other intracranial neoplasms have been associated with breakdown of the blood brain barrier. Other protective CNS barriers have sparsely been studied in brain tumors. Here, we identify the ability of intracranial neoplasms to hijack the meningeal venolymphatic network, which is driven through VEGFR-2/VEGF-A signaling. METHODS C57BL/6J mice were stereotactically injected with syngeneic SB28 (glioblastoma) cell lines. Mice were treated with either isotype control or a VEGFR-2 inhibitor. Two-photon microscopy was used to visualize vascular cytoarchitecture and dynamics in vivo. Meningeal whole mounts, brains and spleens were also collected and analyzed by confocal microscopy and high parameter flow cytometry. Similar experiments were conducted with a PECAM-1 inhibitor to assess the role of endothelial cell crosstalk in venolymphatic expansion. Human dura mater from glioblastoma patients underwent multiplex immunohistochemistry to confirm the translatability of our findings. RESULTS Our imaging studies revealed that glioblastomas can generate an extensive de novo network of meningeal blood vessels and lymphatics both in mice and humans. Lymphatic vessels were often observed developing in parallel to the newly formed vasculature. Intravital two-photon microscopy further revealed that the peritumoral vascular bed in the meninges of mice was leaky, dysfunctional, and generated a hypoxic microenvironment. Importantly, inhibition of VEGFR signaling impeded formation of this faulty venolymphatic network, which slowed tumor growth, reduced peritumoral hypoxia, enhanced immune infiltration, and increased survival. PECAM-1 (CD31) inhibition had a similar effect on the tumor microenvironment, suggesting that endothelial cell crosstalk is required for glioblastomas to optimally invade the meninges. CONCLUSION Our results demonstrate that glioblastomas can invade the meninges and hijack the venolymphatic network through VEGFR-2 and PECAM-1 signaling. While VEGFR-2 is associated with angiogenesis, our data suggest that it may also have an important role in regulating the simultaneous development of de novo meningeal venous and lymphatic drainage during glioblastoma.
NCOG-20. WEARABLE DEVICE DATA QUANTIFY DISEASE PROGRESSION IN HIGH GRADE GLIOMA AND MAY PROVIDE NOVEL OUTCOME MEASURES
Authors: Seema Dadhania, Matthew Williams
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Functional status is a prognostic measure of survival in high grade glioma (HGG). Real-time monitoring between clinical encounters can extend the reach of care and provide actionable insights to drive more personalized and proactive care. We present data from the completed BrainWear Study, a highly novel study evaluating if data captured via a wrist-worn wearable device in patients with HGG can be used to explain, influence and/or predict cancer-related outcomes. Materials and METHODS All participants agreed to wear a wrist-worn Axivity AX3 triaxial accelerometer changed at 14-day intervals. Raw accelerometer data was processed using the UKBiobank Accelerometer analysis package v6.2.3 for Python and inclusion of high-quality wear time selected as ≥72 hours of data over 7-days. We analysed variation in activity by patient demographics and MRI result utilising the Response Assessment in Neuro-Oncology (RANO) criteria. Patient reported outcomes (PROs) were completed at planned study timepoints. Wilcoxin-signed rank test was used to compare participant activity at timepoints of stable or progressive disease (PD). Mixed-effects models were used to evaluate changes in activity. RESULTS 12512 days of accelerometer data were recorded from 56 patients (36 male; 20 female) with a median age of 60 years. 80% of the data were characterised as high-quality. Mean acceleration(mg) and time spent walking daily(h/day) correlated positively with the global health QOL and physical functioning scores and inversely with the fatigue score from PROs. In the 6-weeks surrounding an MRI scan, patients with PD walked on average 1856 steps less per day than those with stable disease, and spent 22 minutes less walking (p=0.0403). Several wearable data daily physical activity measures demonstrated statistically significant change at the time of PD. CONCLUSION Remote monitoring data can complement snapshots of health gathered during clinical visits. Collection of digital data hold promise for novel HGG trial outcome measure development.
RADT-27. BONE MARROW SUPPRESSION AFTER REIRRADIATION THERAPY WITH PROTON VERSUS PHOTON THERAPY FOR RECURRENT GLIOMA
Authors: Varun Subramaniam, Alexander Zhou, Carlos Ortega Rios, Constantinos Hadjipanayis, Stanislav Lazarev, Robert Press
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION High grade radiation-induced lymphopenia has been implicated to worse prognostic outcomes and overall survival in numerous malignancies. Understanding factors which influence lymphopenia can help optimize radiation delivery and overall patient care. Proton therapy (PRT), due to its distinct dose fall-off, spares tissues and organ-contained blood pools from excess radiation compared to conventional photon radiation (XRT) and may thereby reduce hematologic toxicity. METHODS Patients with confirmed glioma diagnosis who underwent reirradiation with either PRT or XRT were retrospectively analyzed. Complete blood counts (CBCs) within one month of reirradiation start, and CBCs within one month of reirradiation completion were reviewed. Values of interest included total white blood cell (WBC), absolute neutrophil count (ANC), and absolute lymphocyte count (ALC). Dosimetric data was collected to assess whole brain mean dose (WBMD), and volume of brain tissue receiving 5-50 Gy (V5-V50). RESULTS 16 patients receiving either PRT (n = 8) or XRT (n = 8) were included. Treatment doses ranged from 35-59.4 Gy. Across all patients there was a decrease in WBC, ANC, and ALC after reirradiation in both PRT and XRT (p &amp;lt; 0.05). Compared to reirradiation with XRT, patients who underwent PRT had significantly lesser reductions in WBC (PRT: 8.60% decrease, XRT: 22.58% decrease; p &amp;lt; 0.05). PRT reirradiation also resulted in lesser ANC and ALC reductions, though did not reach statistical significance. On dosimetric comparison of XRT and PRT plans, PRT demonstrated significant reductions in V5, V10, V20, and V30 (p &amp;lt; 0.05). V5 through V40 and WBMD were significantly correlated with decreased WBC, ANC, and ALC (p &amp;lt; 0.01). CONCLUSION Preliminary results show PRT reirradiation leads to decreased WBMD and volumes of brain tissues receiving 5 to 30 Gy. Given that these parameters are associated with greater reductions in lymphocytic counts, PRT reirradiation may confer reduced hematologic toxicity in patients seeking adjuvant radiation therapy.
MODL-23. PAIRED GLIOBLASTOMA CELL CULTURES OF THE FLUORESCENT BULK TUMOR AND NON-FLUORESCENT TUMOR MARGIN DISPLAY DIFFERENTIAL PHENOTYPES AND CELL STATES ACROSS PATIENTS
Authors: Inês Neves, Nagaprathyusha Maturi, Yonglong Dang, Xi Lu, Francesco Latini, Irem Yildirim, Anders Sundström, Veera Jokinen, Tobias Bergström, Pengwei Xing, Malin Jarvius, Rolf Larsson, Mårten Fryknäs, Mats Ryttlefors, Xingqi Chen, Fredrik Swartling, Lene Uhrbom
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma is a devastating disease with a median survival of 8 months after diagnosis. Over 90% of patients have a recurrence that is in contact with the resection cavity. To understand the potential relapse-causing cells of the local infiltrative tumor margin, which have rarely been studied, we have established and analyzed paired cell cultures from the fluorescent bulk tumor and non-fluorescent tumor margin. Tumor samples were resected using 5-ALA fluorescence-guided surgery and employing stringent procedures to separate margin samples from bulk tumor cells. All margin samples were resected at least 1cm beyond the fluorescent border in non eloquent areas as determined intraoperatively. Bulk and margin samples from 13 glioblastoma patients were explanted and 7 paired cultures that could be maintained to at least passage 7 were established. Analysis of self-renewal and orthotopic tumor formation of both acutely dissociated cells and established cultures showed that bulk tumor cells in all cases had a higher capacity than their paired margin cells. Conversely, margin cells always displayed a higher invasive capacity than their paired bulk tumor cells. Combined single nucleus RNA- and ATAC-sequencing was performed on three paired cultures. Analysis of snRNA-seq data showed that the margin cell phenotype was connected with transitions towards more differentiated (AC- and MES-like) cell states compared to paired bulk tumor cells that showed a higher rate of cells in progenitor cell-like states (NPC- and OPC-like). snATAC analysis uncovered that the margin cell phenotype was connected with transcription factor (TF) motifs known to be involved in cell invasion and differentiation, while paired bulk tumor cells were enriched for TF motifs involved in neural development and proliferation. We present a unique collection of margin cell cultures that we believe are more relevant models of the relapse-causing glioblastoma cells than those established from the bulk tumor.